Objective: We aimed to investigate the hypothesis that amplitudes of compound muscle action potential (CMAP) elicited by single stimulation decrease by baseline neuromuscular blocking in myasthenia gravis (MG), and to examine correlation of CMAP amplitudes with baseline muscle weakness. Methods: One hundred ninety-four consecutive patients who underwent repetitive 3 Hz nerve stimulation tests (RNST) at our laboratory were included in the study. Of these, 109 patients were diagnosed as suffering from MG, and the remaining 85 with other disease served as the non--MG controls. RNST was performed on the nasalis, trapezius, and abductor digiti minimi (ADM) muscles. CMAP amplitudes elicited by the first stimulation were compared between the two groups. In MG patients, we studied the correlation of CMAP amplitudes with MG Foundation of America (MGFA) class, total scores of manual muscle testing (MMT), and 4th decrement (%) of RNST. Results: Compound muscle action potential amplitudes in MG were significantly lower than in controls ( p < 0.05 in all muscles tested). Decreases in CMAP amplitudes were more prominent in generalized than in ocular MG (p < 0.05), and in patients with MGFA III-V classes than in those with 0-II (p < 0.01 in the trapezius and ADM). CMAP amplitudes partially correlated with total MMT scores and MG-ADL scale scores. Additionally, CMAP amplitudes elicited by the first stimulation correlated with the 4th decrement of RNST (p < 0.01 in all muscles tested). Conclusion: Compound muscle action potential amplitudes are reduced in MG, presumably by baseline neuromuscular transmission block, and could reflect persistent muscle weakness, rather than fatigue, in MG patients.

Background and purpose Muscle ultrasonography has been increasingly recognized as a useful tool for detection of fasciculations. Separately, concordance between dominant hand and onset side has been reported in amyotrophic lateral sclerosis (ALS). The aim of this study was to reveal the distribution of fasciculations in the whole body, focusing on handedness. Methods In 106 consecutive patients with ALS, muscle ultrasonography was systematically performed in 11 muscles (the tongue, and bilateral biceps brachii, 1st dorsal interosseous [FDI], T10-paraspinalis, vastus lateralis and tibialis anterior muscles). The fasciculation intensity was scored from 0 to 3 for each muscle. Results Fasciculations were more frequently found in the limb muscles than the tongue and paraspinalis. Side and handedness analyses revealed that fasciculation intensity in FDI was significantly more prominent on the right (median [inter-quartile range] 2 [0 - 3]) than left (1.5 [0 - 3]; p = 0.016), and in the dominant hand (2 [1 - 3]) than non-dominant side (1.5 [0 - 3]; p = 0.025). The differences were greater in patients with upper limb onset. There were no side differences in the lower limb muscles. Multivariate analyses showed that male patients had more frequent fasciculations in the dominant FDI (β = 0.22, p < 0.05). Conclusion More intensive fasciculations are present in the FDI in the dominant hand and gender might be associated with fasciculation intensities. This distribution pattern of fasciculations might be associated with pathogenesis of ALS.

Background Previous studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability has not been fully disclosed. Methods Threshold tracking transcranial magnetic stimulation (TMS) and motor nerve excitability testing were prospectively performed in 53 patients with ALS and 50 healthy subjects, and their relations to compound muscle action potential (CMAP) amplitude and revised ALS Functional Rating Scale were cross-sectionally analysed. Results Compared with controls, patients with ALS showed both cortical and peripheral hyperexcitability; TMS showed reduced short-interval intracortical inhibition (interstimulus interval 1-7 ms) (p<0.001) and shortened silent period (p<0.05), and median nerve excitability testing revealed greater changes in depolarising threshold electrotonus (TEd) and greater superexcitability (p<0.0001, both), suggesting reduced axonal potassium currents. Significant correlations between cortical and peripheral excitability indices were not found. Greater changes in TEd (90-100 ms) (R=-0.33, p=0.03) and superexcitability (R=0.36, p=0.01) were associated with smaller amplitude of CMAP, whereas cortical excitability indices had no correlation with CMAP amplitude. More rapid motor functional decline was associated with only greater TEd (90-100 ms) (beta=0.46, p=0.001). Conclusions Our results suggest that in ALS, cortical excitability is continuously high regardless of the extent of the peripheral burden, but peripheral hyperexcitability is associated with the extent of the peripheral burden and disease evolution speed. Alterations of ion channel function may play an important role in ALS pathophysiology.

Objective: Fatigue is a major disabling problem in patients with neuromuscular disorders. Both nerve demyelination and increased axonal branching associated with collateral sprouting reduce the safety fac-tor for impulse transmission and could cause activity-dependent hyperpolarization and conduction block during voluntary contraction, and thus fatigue. This study aimed to investigate whether activity-dependent conduction block is associated with fatigue in demyelinating neuropathies and lower motor neuron disorders.Methods: This study included 31 patients (17 with chronic inflammatory demyelinating polyneuropathy [CIDP] and 14 with spinal and bulbar muscular atrophy [SBMA]). Sixteen healthy subjects served as nor-mal controls. Fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC). Compound muscle action potential (CMAP) recording and nerve excitability testing after median nerve stimulation in the wrist were performed before and after maximal voluntary contraction of the abductor pollicis brevis for 1 min.Results: Patients with CIDP/SBMA had prominent fatigue with higher FSMC motor scores (P < 0.0001) than normal controls. After voluntary contractions, CMAP amplitudes decreased significantly in four of the 17 patients with CIDP and one of the 14 patients with SBMA. The reduction in CMAP amplitude was associated with the fatigue score in the motor but not in the cognitive domain. After voluntary con-traction, excitability testing showed axonal hyperpolarization in the normal and CIDP/SBMA groups.Conclusions: In CIDP or SBMA, fatigue is caused by voluntary contraction-induced membrane hyperpolar-ization and conduction block, presumably due to the critically lowered safety factor due to demyelination or increased axonal branching.Significance: Peripheral fatigue can be objectively assessed using CMAP amplitudes and nerve excitability testing.(c) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Objective This study aimed to clarify the relationship between progressive medial temporal atrophy and onset subtype in patients with amyotrophic lateral sclerosis (ALS). Methods Medial temporal atrophy, ALS functional rating scale (ALSFRS), and cognitive function were assessed in 119 patients who were grouped into three ALS subtypes: bulbar, upper limb, and lower limb onset. Medial temporal atrophy, represented by a Z-score, was determined using an analysis software of magnetic resonance images known as the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD). Among 119 patients, 60 underwent follow-up VSRAD, ALSFRS, and cognitive testing. The sequential data were compared among onset subtypes. Furthermore, TDP-43 pathology was assessed in 20 autopsied patients (including seven who underwent VSRAD before death) to examine the relationships among medial temporal atrophy, onset subtypes, and severity of the hippocampal TDP-43 pathology. Results Multiple regression analysis revealed that the Z-score at baseline was associated with the age of onset and duration of illness. A high Z-score at baseline and the bulbar/upper limb subtypes affected the progression rate of Z-score. Pathological examination revealed increased hippocampal TDP-43 pathology score associated with bulbar and upper limb subtypes. Moreover, the Z-score before death correlated with the hippocampal TDP-43 pathology score. Conclusion Medial temporal atrophy in ALS is associated with bulbar and upper limb onset subtypes. This progression may be related to the extent of TDP-43 pathology.

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

Introduction. Upper motor neuron signs are mainly assessed by clinical examinations. Threshold tracking transcranial magnetic stimulation (TT-TMS) can precisely investigate motor cortical function and has been reported as a diagnostic marker in amyotrophic lateral sclerosis (ALS). The correlation between TT-TMS and clinical and neurophysiological findings were examined. Methods. TT-TMS was performed in 30 ALS patients and 26 healthy controls (HC), measured in the abductor pollicis brevis (APB) muscle. Clinical factors, such as age, gender, disease duration, site of onset, upper motor neuron (UMN) sign scores and ALS functional rating scale revised (ALSFRS-R) and a neurophysiological index, such as compound muscle action potential (CMAP) amplitude, measured in the APB muscle, were analyzed with TT-TMS findings. Results. Of 30 patients, 13 were male, and 10 were bulbar onset. The mean age was 69 years old, and the mean disease duration was 19 months. Averaged short interval intracortical inhibition (SICI) (1-7 ms) was decreased in ALS (p < 0.01), compared with HC. Averaged SICI (1-7 ms) was not related to age, gender, disease duration, site of onset, UMN sign scores, ALSFRS-R and CMAP amplitudes. Decreased SICI was unveiled even in 4 patients, without evident upper motor neuron signs. Conclusion. TT-TMS found motor cortical dysfunction in ALS, but the relationship between SICI and UMN signs was not evident. Progress of cortical hyperexcitability and pyramidal tract lesion may not be parallel in ALS. Additionally, muscle atrophies might hamper detection of UMN signs. Further studies are necessary to discuss usefulness of TT-TMS as a UMN sign marker in ALS.

INTRODUCTION:In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS:One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS:MG patients showed a significantly greater MCD mean (MG: control, 26.3 μs; 13.5 μs [median]; P < .0001), MCD SD (MG: control, 12.8 μs; 5.1 μs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 μs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms. DISCUSSION:The dispersion of MCD as measured by MCD SD greater than 7.2 μs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease.

Objective The ‘split hand’ sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both cortical and spinal/peripheral excitotoxic mechanisms have been proposed. We aimed to study split hand and axonal excitability in spinal and bulbar muscular atrophy (SBMA) in which cortical motor neurons are intact. Methods In 35 patients with genetically confirmed SBMA, 55 with ALS, 158 with other neuromuscular diseases and 90 normal controls; split hand was strictly determined by amplitudes of compound muscle action potentials. Nerve excitability testing of median motor axons was performed in 35 SBMA and 55 patients with ALS and 45 normal controls. Results Split hand was as frequently found for patients with SBMA (57%) and ALS (62%), compared with disease (20%) and normal (0%) controls. Excitability testing showed that in both SBMA and ALS, strength-duration time constant was longer, and threshold changes in depolarising threshold electrotonus and superexcitability in the recovery cycle were greater than in normal controls (p<0.01). Conclusions Split hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS.

Background and purpose Cranial nerve palsy is occasionally present in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), but its prevalence, characteristics and relations with the CIDP subtypes have rarely been investigated. The aim of this study was to systematically assess cranial nerve involvement in typical and atypical CIDP. Methods Clinical data were reviewed in 132 consecutive patients with CIDP, including typical CIDP (n = 89), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (n = 31), distal acquired demyelinating symmetric (DADS) (n = 9) and others (n = 3). Results The frequency of cranial nerve palsy was 11% in typical CIDP, 48% in MADSAM and 11% in DADS. Facial and bulbar palsy was most frequently present (9%), followed by ocular motor nerve palsy (5%). Bilateral involvement was seen in all typical CIDP and DADS patients, whereas 80% of MADSAM patients had unilateral palsy. The presence of cranial nerve involvement was associated with more severe limb muscle weakness in typical CIDP, but not in MADSAM. Cranial nerve palsy fully recovered in 90% of typical CIDP and in 67% of MADSAM patients. Conclusion Amongst the CIDP subtypes, cranial palsy is frequent and unilateral in MADSAM, and less frequent and bilateral in typical CIDP and DADS. In typical CIDP, facial and bulbar palsy reflects more severe and extensive inflammation.

Objective A randomized controlled trial has shown the efficacy of thalidomide against polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome; however, there are still refractory patients. We studied the effects of lenalidomide, a derivative of thalidomide, on patients refractory to thalidomide. Methods This prospective single-arm trial evaluated the safety and efficacy of lenalidomide plus dexamethasone in refractory or recurrent patients with POEMS syndrome. The regimen was administered as six 28-day cycles with lenalidomide on days 1-21 (15 mg in cycle 1, and 25 mg in cycle 2-6) plus dexamethasone once a week (20 mg). The primary endpoints were the rate of reduction in the serum vascular endothelial growth factor (VEGF) level at 24 weeks and the incidence of adverse events. This trial was registered with ClinicalTrial.gov, NCT02193698. Results Between July 2014 and December 2015, five men were enrolled. All patients had been refractory to thalidomide plus dexamethasone for more than 24 weeks. The mean rate of reduction in the serum VEGF level at 24 weeks was 59.6%±8.3% (p=0.0003). The mean serum VEGF level decreased from 2,466±771 pg/mL to 974±340 pg/mL. No serious adverse events were observed, and all patients completed six cycles treatment. Discussion Lenalidomide is a therapeutic option for thalidomide-refractory patients with POEMS syndrome.

OBJECTIVE:The interpretation of electrophysiological findings may lead to misdiagnosis in polyneuropathies. We investigated the electrodiagnostic accuracy of three supervised learning algorithms (SLAs): shrinkage discriminant analysis, multinomial logistic regression, and support vector machine (SVM), and three expert and three trainee neurophysiologists.METHODS:We enrolled 434 subjects with the following diagnoses: chronic inflammatory demyelinating polyneuropathy (99), Charcot-Marie-Tooth disease type 1A (124), hereditary neuropathy with liability to pressure palsy (46), diabetic polyneuropathy (67), and controls (98). In each diagnostic class, 90% of subjects were used as training set for SLAs to establish the best performing SLA by tenfold cross validation procedure and 10% of subjects were employed as test set. Performance indicators were accuracy, precision, sensitivity, and specificity.RESULTS:SVM showed the highest overall diagnostic accuracy both in training and test sets (90.5 and 93.2%) and ranked first in a multidimensional comparison analysis. Overall accuracy of neurophysiologists ranged from 54.5 to 81.8%.CONCLUSIONS:This proof of principle study shows that SVM provides a high electrodiagnostic accuracy in polyneuropathies. We suggest that the use of SLAs in electrodiagnosis should be exploited to possibly provide a diagnostic support system especially helpful for the less experienced practitioners.

In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.

CIDP is a most common chronic immune-mediated demyelinating neuropathy, but still a rare disease; the reported prevalence ranges from 0.8 to 8.9 per 100 000 people.1 The different prevalence among the studies is partly dependent on diagnostic criteria and CIDP subtypes. Currently, diagnostic criteria proposed by Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) are generally used, and the guideline also classified CIDP into the clinical subtypes; ‘typical CIDP’, and ‘atypical CIDP’ included multifocal CIDP (Lewis-Sumner syndrome), distal CIDP (distal acquired demyelinating symmetric) and other variants.2 Separately the association of CIDP and diabetes mellitus has been a matter of controversy. So far, at least four studies on the association have been published (table 1 …

POEMS (polyneuropathy, organomegaly, endocrinopathy monoclonal gammopathy, and skin changes) syndrome is occasionally associated with Castleman disease (CD) and their prognosis is considered as poorer than that in POEMS alone patients. To elucidate recent prognosis of POEMS syndrome coexisting with CD, we reviewed clinical data of 102 patients with POEMS syndrome treated at our institution between 2000 and 2018 and compared clinical characteristics, response to treatment, and prognosis between POEMS patients with biopsy-proven CD (POEMS-CD) and those without it. Fourteen POEMS-CD patients and 56 POEMS alone patients were identified, and the remaining 32 patients with unbiopsied lymphadenopathy were excluded. POEMS-CD patients significantly showed earlier onset and less severe neuropathic symptoms. Most of the POEMS-CD patients were treated with thalidomide and dexamethasone (n = 10, 71%), and subsequently received autologous stem cell transplantation (n = 6, 43%). Response to thalidomide was better in patients with POEMS-CD than those with POEMS alone (90% vs 43% clinical response, [p = .012]; 80% vs 45% normalization of serum VEGF levels, [p = .079]). The 10-year overall survival (95% confidence interval) was 89% (50-98%) in POEMS-CD patients and 61% (42-77%) in those with POEMS alone. POEMS syndrome associated with CD constitutes a subgroup of POEMS syndromes characterized by earlier onset, mild polyneuropathy, and favorable response to treatment. Recognition of this subgroup is significant for determination of therapeutic strategy.